Cell Signaling

1. Cell Signaling

2. Modes of Cell-Cell Signaling • Endocrine signaling is a type of cell-cell signaling in which endocrine cells secrete hormones that are carried through the circulation to distant target cells. • Paracrine signaling is local cell-cell signaling in which a molecule released by one cell acts on a neighboring target cell. • Autocrine signaling is a type of cell signaling in which a cell produces a growth factor to which it also responds.

3. Modes of Cell-Cell Signaling • All signaling molecules act by binding to receptors expressed by their target cells. • Steroid family and nuclear receptor family • Growth factors, peptide hormones and neuropeptides • Neurotransmitters

4. Steroid Hormones and the Nuclear Receptor Superfamily • Hormones are signaling molecules that are produced by endocrine glands that act on cells at distant body sites. • Steroid hormones are a group of hydrophobic hormones that are derivatives of cholesterol. • Testosterone is a steroid hormone produced by the testis.

5. Steroid Hormones and the Nuclear Receptor Superfamily • Estrogen and progesterone are steroid hormones produced by the gonads. • Corticosteroids are steroid hormones produced by the adrenal gland. • Glucocorticoids are steroids produced by the adrenal gland that act to stimulate production of glucose. • Mineralocorticoids are steroid hormones produced by the adrenal gland that act on the kidney to regulate salt and water balance. • Thyroid hormone is synthesized from tyrosine in the thyroid gland and it plays important roles in development and regulation of metabolism. • Vitamin D3 regulates Ca2+ metabolism and bone growth. • Retinoic acid is a signaling molecule synthesized from vitamin A. Retinoids play important roles in vertebrate development and are synthesized from vitamin A. • The nuclear receptor superfamily is a family of transcription factors that includes the receptors for steroid hormones, thyroid hormone, retinoic acid, and vitamin D3.

6. Steroid Hormones and the Nuclear Receptor Superfamily • Ligand binding has distinct effects on different receptors. • Estrogen and progesterone are steroid hormones produced by the gonads.

7. 15.4 Gene regulation by the thyroid hormone receptor • Receptors might bind DNA in either the presence or absence of a hormone, but hormone binding alters the activity of the receptor as a transcriptional regulatory molecule. • Thyroid hormone is synthesized from tyrosine in the thyroid gland and it plays important roles in development and regulation of metabolism.

8. Types of Signaling Molecules • Neurotransmitters carry signals between neurons or from neurons to other types of target cells, such as muscle cells. • Because the neurotransmitters are hydrophilic molecules they are unable to cross the plasma membrane.

9. Peptide Hormones and Growth Factors • The widest variety of signaling molecules in animals are peptides, ranging in size from only a few to more than a hundred amino acids. • Peptide hormones are signaling molecules composed of amino acids. • Neuropeptides are secreted by some neurons instead of small-molecule neurotransmitters.

10. Peptide Hormones and Growth Factors • Enkephalins and endorphins are neuropeptides that act as a natural analgesic. • Growth factors are polypeptides that control animal cell growth and differentiation. • Nerve growthfactor, or NGF, regulates the development and survival of neurons. • Neurotrophins are members of a family of polypeptides that regulate neuron development and survival. • Epidermal growth factor, or EGF, stimulates cell proliferation. • Platelet-derived growth factor, or PDGF, stimulates the proliferation of fibroblasts in the vicinity of blood clots, thereby contributing to re-growth of the damaged tissue.

11. Peptide Hormones and Growth Factors • Cytokines regulate the development and differentiation of blood cells and control the activities of lymphocytes during the immune response. • Membrane-anchored growth factors function specifically as signaling molecules during direct cell-cell interactions. • Eicosanoids are a class of lipids, including prostaglandins, prostacyclins, thromboxanes, and leukotrienes, that act in autocrine and paracrine signaling. • Prostaglandins are a family of eicosanoid lipids involved in signaling inflammation.

12. Ligands Signal through Membrane Receptors • Most ligands responsible for cell-cell signaling bind to receptors on the surface of their target cells. • G-coupled receptors • Protein Receptor Tyrosine Kinases • Cytokine Receptors and Non-receptor Tyrosine kinases • Ligand binding to a receptor on the surface of the cell initiates a chain of intracellular reactions, ultimately reaching the target cell nucleus and resulting in programmed changes in gene expression.

13. Functions of Cell Surface Receptors • G proteins are guanine nucleotide-binding proteins that assist in transmitting signals to intracellular targets. • G protein-coupled receptors are structurally and functionally related proteins characterized by seven membrane-spanning a helices. • cAMP is an important second messenger that mediates cellular responses to a variety of hormones.

14. G Protein-Coupled Receptors • G proteins consist of three subunits designated α, β, and . • Heterotrimeric G proteins are guanine nucleotide-binding proteins that consist of three subunits. • In addition to regulating target enzymes, both the α and β subunits of some G proteins directly regulate ion channels.

15. 15.13 Regulation of G proteins

16. Receptor Protein-Tyrosine Kinases • Receptor protein-tyrosine kinases phosphorylate their substrate proteins on tyrosine residues. • The human genome encodes 59 receptor protein-tyrosine kinases, including the receptors for EGF, NGF, PDGF, insulin, and many other growth factors.

17. Receptor Protein-Tyrosine Kinases • The first step in signaling from most receptor protein-tyrosine kinases is ligand-induced receptor dimerization. • Autophosphorylation is a reaction in which a protein kinase catalyzes its own phosphorylation. • The association of downstream signaling molecules with receptor protein-tyrosine kinases is mediated by protein domains that bind to specific phosphotyrosine-containing peptides.

18. Receptor Protein-Tyrosine Kinases • An SH2 domain binds to specific short peptide sequences containing phosphotyrosine residues. • PTB domains are protein domains that bind phosphotyrosine-containing peptides.

19. Cytokine Receptors and Nonreceptor Protein-Tyrosine Kinases • The cytokine receptor superfamily is a family of cell surface receptors that act by stimulating the activity of intracellular protein-tyrosine kinases. • Non-receptor protein-tyrosine kinases are intracellular protein-tyrosine kinases. • The first step in signaling from cytokine receptors is thought to be ligand-induced receptor dimerization and cross-phosphorylation of the associated non-receptor protein-tyrosine kinases.

20. Pathways of Intracellular Signal Transduction • Many cell surface receptors stimulate intracellular target enzymes, which may be either directly linked or indirectly coupled to receptors by G proteins. • Intracellular signal transduction is a chain of reactions that transmits chemical signals from the cell surface to their intracellular targets. • Cyclic AMP, or cAMP, is adenosine monophosphate in which the phosphate group is covalently bound to both the 3’ and 5’ carbon atoms, forming a cyclic structure; it’s an important second messenger in the response of cells to a variety of hormones. • A second messenger is a compound whose metabolism is modified as a result of a ligand-receptor interaction; it functions as a signal transducer by regulating other intracellular processes.

21. The cAMP Pathway: Second Messengers and Protein Phosphorylation • Adenylyl cyclase is an enzyme that catalyzes the formation of cyclic AMP from ATP. • cAMP phosphodiesterase is an enzyme that degrades cyclic AMP. • cAMP-dependent protein kinase, or protein kinase A, binds to regulatory subunits, leading to their dissociation from catalytic subunits.

22. The cAMP Pathway: Second Messengers and Protein Phosphorylation • In the regulation of glycogen metabolism, protein kinase A phosphorylates two key target enzymes.

23. The cAMP Pathway: Second Messengers and Protein Phosphorylation • cAMP response element, or CRE, is a regulatory sequence that mediates the transcriptional response of target genes to cAMP. • CREB is a cyclic AMP response element-binding protein and transcription factor that is activated by cAMP-dependent protein kinase. • Protein kinases, such as protein kinase A, do not function in isolation within the cell.

24. Cyclic GMP • Cyclic GMP, or cGMP, is an important second messenger in animal cells. • Rhodopsin is a G protein-coupled receptor in retinal rod cells that activates transducin in response to light absorption. • Transducin is a G protein that stimulates cGMP phosphodiesterase when it is activated by rhodopsin. • cGMP phosphodiesterase is an enzyme that degrades cGMP.

25. Phospholipids and Ca2+ • Phosphatidylinositol 4,5-bisphosphate, or PIP2, is a minor component of the plasma membrane, localized to the inner leaflet of the phospholipid bilayer. • Phospholipase C is an enzyme that hydrolyzes PIP2 to form the second messengers diacylglycerol and inositol trisphosphate.

26. The PI 3-Kinase/Akt and mTOR Pathways • Phosphatidylinositide (PI) 3-kinase is an enzyme that phosphorylates PIP2, yielding the second messenger phosphatidylinositol 3,4,5-trisphosphate, or PIP3. • Phosphatidylinositol 3,4,5-trisphosphate, or PIP3, is a second messenger formed by phosphorylation of PIP2.

27. The PI 3-Kinase/Akt and mTOR Pathways • Akt is a protein-serine/threonine kinase that is activated by PIP3 and plays a key role in signaling cell survival. • In its activated form, Akt phosphorylates a number of target proteins.

28. MAP Kinase Pathways • MAP kinases are activated in response to a variety of growth factors and other signaling molecules. • ERK is a member of the MAP kinase family that plays a central role in growth factor-induced cell proliferation. • Ras is a GTP-binding protein that couples growth factor receptors to intracellular targets.

29. MAP Kinase Pathways • Guanine nucleotide exchange factors stimulate the release of bound GDP and its exchange for GTP. • GTPase-activating proteins stimulate GTP hydrolysis by the small GTP-binding proteins.

30. 15.38 Pathways of MAP kinase activation in mammalian cells

31. NF-kB Signaling • The NF-κB family of transcription factors play key roles in the immune system and in inflammation as well as in regulation of proliferation and survival of many types of animal cells. • IκB is an inhibitory subunit of the NF-κB transcription factor.

32. Feedback and Crosstalk • Signaling pathways do not operate in isolation; rather, there is frequent crosstalk between different pathways, so that intracellular signal transduction ultimately needs to be understood as an integrated network of connected pathways. • Feedback loops are similar in principal to feedback regulation of metabolic pathways in that they control the activity of signaling pathways.

33. 15.50 Crosstalk between G protein-coupled receptors and ERK signaling by b-arrestin • Crosstalk refers to the interaction of one signaling pathway with another. • β-arrestins are regulatory proteins that terminate signaling from G protein-coupled receptors, as well as stimulate other downstream signaling pathways.

34. Networks of Cellular Signal Transduction • Feedforward relays are regulatory mechanisms in which one element of a signaling pathway stimulates a downstream component. • Many signaling pathways involve receptors that stimulate cascades of protein kinases that ultimately affect gene expression by regulating transcription factors.